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EP1042689B1 - Device for digital subtraction angiography - Google Patents

Device for digital subtraction angiography Download PDF

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Publication number
EP1042689B1
EP1042689B1 EP98966282A EP98966282A EP1042689B1 EP 1042689 B1 EP1042689 B1 EP 1042689B1 EP 98966282 A EP98966282 A EP 98966282A EP 98966282 A EP98966282 A EP 98966282A EP 1042689 B1 EP1042689 B1 EP 1042689B1
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EP
European Patent Office
Prior art keywords
resistance
arrangement according
input
voltage
operational amplifier
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EP98966282A
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German (de)
French (fr)
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EP1042689A1 (en
Inventor
Hans Jürgen BESCH
Michael Lohmann
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Deutsches Elektronen Synchrotron DESY
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Deutsches Elektronen Synchrotron DESY
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/482—Diagnostic techniques involving multiple energy imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/40—Arrangements for generating radiation specially adapted for radiation diagnosis
    • A61B6/4064—Arrangements for generating radiation specially adapted for radiation diagnosis specially adapted for producing a particular type of beam
    • A61B6/4092—Arrangements for generating radiation specially adapted for radiation diagnosis specially adapted for producing a particular type of beam for producing synchrotron radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/48—Diagnostic techniques
    • A61B6/481—Diagnostic techniques involving the use of contrast agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/504—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of blood vessels, e.g. by angiography

Definitions

  • the invention relates to an arrangement according to the preamble of Claim 1.
  • the two X-rays are focused on the heart of a patient and behind them hit a detector with two counting chambers arranged in parallel and at a distance from one another, whose signals are converted into digital signals via a charge-sensitive A / D converter and sent to a computer, which then displays one image each Energy E 1 and an image of the energy E 2 is composed and the images are subtracted logarithmically.
  • the displayed image is displayed on a monitor.
  • DE 39 01 837 A1 discloses a radiation detector, which in is capable of local distribution of high beam intensities with high accuracy, a large dynamic range and high sensitivity in short recording times. Applications are, for example, in medical diagnostics for snapshots of fast moving parts (coronary arteries). Pulsed radiation sources are used for this, the Individual quantum signals belonging to a beam pulse in a proportional chamber can be summed up and thus obtained Individual signals per radiation source pulse either already represent wanted intensity signal or electronically pro Pixel added up over a number of radiation source pulses become.
  • DE 39 01 837 A1 also shows the constructive Structure of such a detector. The disadvantage of this Detector, however, is that together with conventional Amplifier and converter circuits the required Image resolution can not be achieved.
  • the object of the invention is the arrangement of the aforementioned Kind of improving in that the resolution of the received Image is better, especially coronary arteries can be represented more clearly.
  • FIG. 1 shows as the X-ray radiation source, for example, a storage ring such as that which is available to the applicant as DORIS.
  • the circulating positron beam e + between the poles of a so-called Wiggler magnet is deflected back and forth in one plane, for example in the manner shown, by pole pairs connected in series but reversed in polarity, which leads to strong synchrotron radiation formation.
  • This synchrotron radiation is a polychromatic or "white" beam 7, which is directed to a monochromator 1 through a system of collimators and diaphragms (not shown).
  • the monochromator 1 is located approximately 15 to 36 m from the Wiggler magnet 2, which forms the source point of the radiation.
  • the "white" beam 7 has an approximately elliptical cross-section near its source point, the small axis of which is approximately 2 mm long, while the length of the horizontal large axis is approximately 4 mm. Due to beam diaphragms and natural divergence, the beam 7 has a horizontal width of approximately 100 mm and a height of approximately 2.5 mm at the location of the monochromator 1. Using a double monochromator 1 results in two monochromatic beams with an energy of E 1 and E 2 . The monochromatic beams E 1 and E 2 arrive at the input of a detector 3, passing through the heart 10 of a patient on their way during operation. At the entrance of the detector 3 they have a distance of 1.5 mm and a horizontal width of currently 120 mm and a height of 1.0 mm each.
  • the detector 3 has two ionization chambers 31, 32 with connected detection circuits 51, 52.
  • the output signals from the detection circuits 51, 52 of the detector 3 are transmitted via lines 511, 512 to a computer system 6 which controls the image evaluation in a manner known per se, for example in accordance with DE 35 17 101 C1, by in each case an image of the energy Subtracts E 1 from a second image of energy E 2 and displays the image obtained on a monitor 20.
  • a patient sits on a chair 9 which can be moved up and down in a controlled manner by means of hydraulics. This is indicated by the double arrow.
  • the chair 9 performs an upward movement of approximately 40 cm, the first 10 cm used to accelerate the chair 9 and the patient sitting on it, the subsequent 20 cm of its path to movement at a constant speed of 50 cm / sec and the last 10 cm for braking.
  • the patient's organ to be examined for example the heart 10 is moved by the two monochromatic beams E 1 and E 2 in a time of 250 msec.
  • One and the same examination location is imaged so quickly in succession with the beam E 1 and the beam E 2 that the two beam images can be easily subtracted in the computer system 6.
  • a safety system 8 is provided in the beam path of the two X-rays between the monochromator 1 and the detector 3 before the intersection of the two beams E 1 , E 2 and thus in front of the heart 10 to be examined, which has very fast beam closures which Shut off X-rays E 1 and E 2 in less than 10 msec.
  • Such security systems have been used in the operation of our synchrotron for many years.
  • the chair 9 is also controlled via the computer system 6, without this being particularly indicated in the drawing. However, it does not present any difficulties to the person skilled in the art Hydraulics shown for lifting and lowering the chair 9 to be controlled by the computer system 6.
  • FIG. 2 shows a vertical section through the detector 3 of FIG Figure 1, the two ionization chambers 31, 32, each with one Board 311 and 312 and a common drift cathode 313 formed is.
  • the two ionization chambers 31, 32 are enclosed by a housing 33 which is essentially rectangular and has a fastening flange 36 on one side.
  • An inlet channel 37 of approximately 10 mm in height, 150 mm in width and approximately 30 mm in length passes through a wall of the housing 33 and carries at its free end a known collimator 34 through which the two beams E 1 and E 2 can enter.
  • the inner end of the channel 37 is closed by a carbon fiber window (35).
  • an ionizing gas such as krypton or xenon
  • an extinguishing gas e.g. Carbon dioxide filled under a pressure of 10 to 20 bar.
  • the partial pressure ratio of ionization gas to extinguishing gas is about 90:10.
  • each ionization chamber 32 has a glass fiber reinforced one Board 311, 312, which is approximately at a distance of 9mm are arranged to each other.
  • the boards 311, 312 are gold-plated copper strips as anode strips arranged, which run in the beam direction and in 400 ⁇ m grid are arranged.
  • In the right part of Figure 2 is the part highlighted by a dash-dotted circle of the boards 311, 312 shown enlarged.
  • the drift cathode 313 has a thickness of 1.0 mm, during the Distance between drift cathode 313 and each circuit board 311, 312 Is 4.0 mm.
  • the two fresh grids 315 are then each at a distance of 1.0mm to the boards 311, 312 and thus at a distance of 3.0 mm each to the surface of the drift cathode 313 arranged.
  • Fresh grids consist of special wires in the Distance of 0.5 mm that formed in the ionization chambers 31, 32 Shield ions from the anode strips.
  • the first and second boards 311, 312 are in the beam direction led out of the housing 33 of the detector 3 and are at their ends each connected to a detection circuit 51, 52. It is clear that the housing 33 of the detector 3 is closed must be to include the ionizing gas and the quenching gas to be able to. For this purpose is between the boards 311, 312 introduced a plug 38 which the two boards 311, 312 gas-tightly connected to one another, for example by that it is glued to the boards 311, 312. The two boards 311, 312 are in turn gas-tight with the wall of the housing 33 connected, for example also by gluing.
  • each board 311, 312 arranged as gold-plated anodes Copper strips with a grid of 400 ⁇ m from the housing 33 of the detector 3 led out, namely in the form of 336 parallel Stripes, which are arranged at a distance of about 0.3mm and the each have a width of about 0.4mm.
  • the length of each board 311, 312 is approximately 230mm, while the length of the ionization chambers 31, 32 makes up about 60mm.
  • the anode strips run inside the ionization chambers 31, 32 over a length of about 56mm in parallel as they diverge outside the ionization chambers 31, 32 and in particular outside the housing 33 of the detector 3 to such a Distance are widened in the detection circuit 51 and 52 electronic circuit 50 on each anode strip. 3 can be connected.
  • FIG. 3 shows one of the 2 x 336 electronic circuits 50, their input IN to one of the 2 x 336 anode strips on the circuit boards 311 or 312 is connected.
  • the input IN the electronic Circuit 50 leads to the negative input of an operational amplifier OPA, the positive input of which is on ground.
  • the operational amplifier OPA is a type OPA 129 UB, which by the Burr-Brown is manufactured. It becomes normal with ⁇ 15 V operated and is a very low-noise operational amplifier.
  • a transistor T with its emitter is connected to the output of the operational amplifier OPA, specifically via a first resistor R 1 of 5.1 k ⁇ .
  • a DC voltage source S which provides a DC voltage of -4 V.
  • the collector of the transistor T is at a point P, which sees voltages from 0 to about 90 V in operation. For this reason, the transistor T is a voltage-resistant transistor, which is used as a basic circuit.
  • the collector of transistor T feeds back via point P and a second resistor R 2 of 150 M ⁇ to the negative input of the operational amplifier OPA.
  • a high DC voltage of 100 V or more is applied to the point P of the electronic circuit 50, specifically via a third resistor R 3 of 43 k ⁇ , for example.
  • the operational amplifier OPA keeps the differential voltage at its input at almost zero volts, so that the current i s from the input signal via the resistor R 2 to the point P and from there via a fourth resistor R 4 of 30 M ⁇ to an analog-to-digital converter ADC flows.
  • the analog-digital converter is a module of the DDC 101 U type from Burr-Brown with a resolution of 20 bits. This chip was specially designed for reading photodiodes, in which the positive charges or holes are read out. In its unipolar mode, it can therefore only be used to convert positive charge signals into 20-bit signals.
  • the DDC 101 U chip can also be used in bipolar operation, but this reduces the output to 19 bits. In this mode, the noise of the chip is so high that it cannot be used in the present case of image display.
  • the DDC 101 U chip only the unipolar operation of the DDC 101 U chip is suitable for the present application, but the difficulty then lies in the fact that the chip can only process positive charges (holes), while only from the ionization chambers 31, 32 via the anode strips negative charges, namely electrons, are supplied. It is therefore essential for the invention that the negative charges that arrive at the input of the operational amplifier OPA are turned into positive charges that can be processed by the special analog-digital converter ADC of the DDC 101 U type. To do this, it is first necessary to make the resistance R 4 > 20 M ⁇ at the input of the analog-digital converter, because with resistances smaller than 20 M ⁇ , the DDC 101 U chip generates a larger noise than the resistance noise, which is also known as Nyquist Noise is called. If the noise already produces 4 bits, then there are only 16 bits left for image display, which is too little to achieve the required image resolution.
  • the voltage-proof transistor T is placed in the basic circuit between the operational amplifier OPA and the point P.
  • the basic circuit effects a voltage amplification, the transistor T opening up to such an extent that the voltage drop across the second resistor R 2 ensures that the voltage difference at the input of the operational amplifier OPA is zero or almost zero.
  • the charges arriving at the operational amplifier OPA also arrive at the input of the analog-digital converter, in five times the amplification, since the resistance R 2 is selected five times as large as the resistance R 4 .
  • R 2 150 M ⁇
  • R 4 30 M ⁇ .
  • the signal currents supplied by the ionization chambers 31, 32 on the anode strips are otherwise in the range of 100 fA or less, ie i max ⁇ 100 x 10 -15 A. These currents are so low that they correspond to individual 33 keV photons.

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Abstract

The invention relates to a device for digital subtraction angiography in an energy subtraction mode with a special electronic circuit.

Description

Die Erfindung betrifft eine Anordnung gemäß Oberbegriff des Patentanspruchs 1.The invention relates to an arrangement according to the preamble of Claim 1.

Eine derartige Anordnung ist bereits aus der DE 35 17 101 C1 bekannt. Sie dient zur Untersuchung des Herzens mit dem Ziel der Feststellung, ob ein akuter Verschluß eines Herzkranzgefäßes durch ein Blutgerinsel zu befürchten ist. Zu diesem Zweck wird dem Patienten ein Jodkontrastmittel in eine Armvene injiziert und der Patient wird zeilenweise gleichzeitig mit zwei zeilenförmig kollimierten Röntgenstrahlen bestrahlt, von denen der eine eine Energie E1 knapp unterhalb der Jod-Absorptionskante von 33 keV und der andere eine Energie E2 knapp oberhalb der Jod-Absorptionskante hat. Die beiden Röntgenstrahlen werden auf das Herz eines Patienten fokussiert und treffen dahinter auf einen Detektor mit zwei parallel im Abstand zueinander angeordneten Zählkammern, deren Signale über einen Ladungsempfindlichen A/D-Wandler in digitale Signale umgesetzt und einem Rechner zugeleitet, der dann jeweils ein Bild der Energie E1 und ein Bild der Energie E2 zusammensetzt und die Bilder logarithmisch voneinander subtrahiert. Das erhaltene Bild zeigt er auf einem Monitor an.Such an arrangement is already known from DE 35 17 101 C1. It is used to examine the heart with the aim of determining whether an acute occlusion of a coronary artery by a blood clot is to be feared. For this purpose, the patient is injected with an iodine contrast medium in an arm vein and the patient is irradiated line by line simultaneously with two line-shaped collimated X-rays, one of which has an energy E 1 just below the iodine absorption edge of 33 keV and the other an energy E 2 above the iodine absorption edge. The two X-rays are focused on the heart of a patient and behind them hit a detector with two counting chambers arranged in parallel and at a distance from one another, whose signals are converted into digital signals via a charge-sensitive A / D converter and sent to a computer, which then displays one image each Energy E 1 and an image of the energy E 2 is composed and the images are subtracted logarithmically. The displayed image is displayed on a monitor.

Die DE 39 01 837 A1 offenbart einen Strahlungsdetektor, der in der Lage ist, die örtliche Verteilung hoher Strahlintensitäten mit hoher Genauigkeit, einem großen dynamischen Bereich und hoher Empfindlichkeit in kurzen Aufnahmezeiten zu vermessen. Anwendungen liegen zum Beispiel in der medizinischen Diagnostik für Momentaufnahmen schnellbewegter Teile (Herzkranzgefäße). Hierzu werden gepulste Strahlungsquellen verwendet, wobei die Signale der Einzelquanten, die zu einem Strahlimpuls gehören, in einer Proportionalkammer summiert werden und diese so gewonnenen Einzelsignale pro Strahlungsquellen-Puls entweder bereits das gesuchte Intensitätssignal darstellen oder elektronisch pro Bildpunkt über eine Anzahl von Strahlungsquellen-Pulsen aufsummiert werden. Die DE 39 01 837 A1 zeigt weiterhin den konstruktiven Aufbau eines solchen Detektors. Der Nachteil dieses Detektors besteht jedoch darin, daß sich zusammen mit herkömmlichen Verstärker- und Wandlerschaltungen die erforderliche Bildauflösung nicht erreichen läßt.DE 39 01 837 A1 discloses a radiation detector, which in is capable of local distribution of high beam intensities with high accuracy, a large dynamic range and high sensitivity in short recording times. Applications are, for example, in medical diagnostics for snapshots of fast moving parts (coronary arteries). Pulsed radiation sources are used for this, the Individual quantum signals belonging to a beam pulse in a proportional chamber can be summed up and thus obtained Individual signals per radiation source pulse either already represent wanted intensity signal or electronically pro Pixel added up over a number of radiation source pulses become. DE 39 01 837 A1 also shows the constructive Structure of such a detector. The disadvantage of this Detector, however, is that together with conventional Amplifier and converter circuits the required Image resolution can not be achieved.

Aufgabe der Erfindung ist es, die Anordnung der eingangs genannten Art dahingehend zu verbessern, daß die Auflösung des erhaltenen Bildes besser ist, damit insbesondere Herzkranzgefäße deutlicher dargestellt werden können.The object of the invention is the arrangement of the aforementioned Kind of improving in that the resolution of the received Image is better, especially coronary arteries can be represented more clearly.

Zur Lösung dieser Aufgabe dient eine Anordnung mit den Merkmalen des Patentanspruchs 1.An arrangement with the features serves to solve this problem of claim 1.

Sie enthält einen hochempfindlichen Verstärker und Analog-Digital-Wandler mit sehr hoher Dynamik, mit dem die hohen Absorptionsunterschiede im jodgefüllten Körper linear dargestellt werden können. Auf diese Weise ist es möglich, alle drei Herzkranzgefäße trotz Überlagerung durch jodgefüllte Herzkammern darzustellen.It contains a highly sensitive amplifier and analog-digital converter with very high dynamics with which the high absorption differences represented linearly in the iodine-filled body can be. In this way it is possible to have all three coronary arteries despite overlay by iodine-filled heart chambers display.

In diesem Zusammenhang wird darauf hingewiesen, daß die Abbildung der Herzkranzgefäße deswegen so schwierig ist, weil sich einerseits das Herz andauernd bewegt und andererseits das Kontrastmittel sowohl in die Herzkammern als auch in die Herzkranzgefäße gelangt.In this context, it should be noted that the figure the coronary arteries is so difficult because on the one hand the heart is constantly moving and on the other hand the contrast medium both in the ventricles and in the coronary arteries arrives.

Zur Lösung der gestellten Aufgabe war es also erforderlich, für die verwendeten elektronischen Schaltungen einen geeigneten Baustein in Form eines Strom- bzw. Ladungs-Digital-Wandlers zu finden, der einen dynamischen Bereich von mindestens 18 Bit hat, um eine hinreichend gute Auflösung in Form von Farb- oder Kontrastunterschieden zu erreichen. To solve the task it was therefore necessary for the electronic circuits used are suitable Module in the form of a current or charge digital converter find that has a dynamic range of at least 18 bits, a sufficiently good resolution in the form of color or contrast differences to reach.

Die Erfindung wird im folgenden anhand von Figuren näher erläutert; es zeigt

Figur 1
eine schematische Anordnung der Vorrichtung im Strahlengang der Röntgenstrahlung eines Synchrotrons;
Figur 2
eine schematische Schnittansicht des bei der Anordnung gemäß Figur 1 verwendeten Detektors; und
Figur 3
ein Schaltbild einer in dem Detektor aus den Figuren 1 und 2 verwendeten elektronischen Schaltung.
The invention is explained in more detail below with reference to figures; it shows
Figure 1
a schematic arrangement of the device in the beam path of the x-rays of a synchrotron;
Figure 2
is a schematic sectional view of the detector used in the arrangement of Figure 1; and
Figure 3
a circuit diagram of an electronic circuit used in the detector of Figures 1 and 2.

Figur 1 zeigt als Röntgenstrahlungsquelle beispielsweise einen Speicherring, wie er als DORIS bei der Anmelderin vorhanden ist. Dabei wird der umlaufende Positronenstrahl e+ zwischen den Polen eines sogenannten Wiggler-Magneten etwa in der dargestellten Weise durch jeweils hintereinander geschaltete, in der Polarität aber umgekehrte Polpaare in einer Ebene hin und her abgelenkt, was zu einer starken Synchrotronstrahlungsbildung führt. Diese Synchrotronstrahlung ist ein polychromatischer oder "weißer" Strahl 7, der durch ein nicht dargestelltes System von Kollimatoren und Blenden auf einen Monochromator 1 geleitet wird. Der Monochromator 1 befindet sich im Falle von DORIS etwa 15 bis 36m von dem Wiggler-Magneten 2 entfernt, der den Quellpunkt der Strahlung bildet. Der "weiße" Strahl 7 hat in der Nähe seines Quellpunktes einen etwa elliptischen Querschnitt, dessen kleine Achse etwa 2 mm lang ist, während die Länge der horizontal liegenden großen Achse etwa 4 mm beträgt. Durch Strahlblenden und natürliche Divergenz hat der Strahl 7 am Ort des Monochromators 1 eine horizontale Breite von ungefähr 100mm und eine Höhe von ungefähr 2,5mm. Durch Verwendung eines zweifachen Monochromators 1 entstehen daraus zwei monochromatische Strahlen mit einer Energie von E1 und E2. Die monochromatischen Strahlen E1 und E2 gelangen an den Eingang eines Detektors 3, wobei sie auf ihrem Wege im Betrieb das Herz 10 eines Patienten durchlaufen. Am Eingang des Detektors 3 haben sie einen Abstand von 1,5mm und eine horizontale Breite von zur Zeit 120mm und jeweils eine Höhe von 1,0mm.FIG. 1 shows as the X-ray radiation source, for example, a storage ring such as that which is available to the applicant as DORIS. The circulating positron beam e + between the poles of a so-called Wiggler magnet is deflected back and forth in one plane, for example in the manner shown, by pole pairs connected in series but reversed in polarity, which leads to strong synchrotron radiation formation. This synchrotron radiation is a polychromatic or "white" beam 7, which is directed to a monochromator 1 through a system of collimators and diaphragms (not shown). In the case of DORIS, the monochromator 1 is located approximately 15 to 36 m from the Wiggler magnet 2, which forms the source point of the radiation. The "white" beam 7 has an approximately elliptical cross-section near its source point, the small axis of which is approximately 2 mm long, while the length of the horizontal large axis is approximately 4 mm. Due to beam diaphragms and natural divergence, the beam 7 has a horizontal width of approximately 100 mm and a height of approximately 2.5 mm at the location of the monochromator 1. Using a double monochromator 1 results in two monochromatic beams with an energy of E 1 and E 2 . The monochromatic beams E 1 and E 2 arrive at the input of a detector 3, passing through the heart 10 of a patient on their way during operation. At the entrance of the detector 3 they have a distance of 1.5 mm and a horizontal width of currently 120 mm and a height of 1.0 mm each.

Der Detektor 3 weist zwei Ionisationskammern 31, 32 mit angeschlossenen Nachweis-Schaltungen 51, 52 auf. Die Ausgangssignale aus den Nachweis-Schaltungen 51, 52 des Detektors 3 werden über Leitungen 511, 512 an ein Rechnersystem 6 übertragen, das die Bildauswertung in an sich bekannter Weise, beispielsweise gemäß DE 35 17 101 C1 steuert, indem es jeweils ein Bild der Energie E1 von einem zweiten Bild der Energie E2 abzieht und das erhaltene Bild auf einem Monitor 20 anzeigt.The detector 3 has two ionization chambers 31, 32 with connected detection circuits 51, 52. The output signals from the detection circuits 51, 52 of the detector 3 are transmitted via lines 511, 512 to a computer system 6 which controls the image evaluation in a manner known per se, for example in accordance with DE 35 17 101 C1, by in each case an image of the energy Subtracts E 1 from a second image of energy E 2 and displays the image obtained on a monitor 20.

Im Betrieb der erfindungsgemäßen Anordnung sitzt ein Patient auf einem Stuhl 9, der sich durch eine Hydraulik in gesteuerter Weise aufwärts und abwärts bewegen läßt. Dies ist durch den Doppelpfeil angedeutet. In einer Ausführungsform führt der Stuhl 9 eine Aufwärtsbewegung von etwa 40 cm durch, wobei die ersten 10 cm zur Beschleunigung des Stuhls 9 und des darauf sitzenden Patienten dienen, die anschließenden 20 cm seines Weges zur Bewegung mit konstanter Geschwindigkeit von 50 cm/sec und die letzten 10 cm zur Abbremsung dienen. Dadurch wird das zu untersuchende Organ des Patienten, beispielsweise das Herz 10, in einer Zeit von 250 msec durch die beiden monochromatischen Strahlen E1 und E2 bewegt. Ein und derselbe Untersuchungsort wird dabei so schnell hintereinander mit dem Strahl E1 und dem Strahl E2 abgebildet, daß sich die beiden Strahlbilder im Rechnersystem 6 ohne weiteres subtrahieren lassen.In the operation of the arrangement according to the invention, a patient sits on a chair 9 which can be moved up and down in a controlled manner by means of hydraulics. This is indicated by the double arrow. In one embodiment, the chair 9 performs an upward movement of approximately 40 cm, the first 10 cm used to accelerate the chair 9 and the patient sitting on it, the subsequent 20 cm of its path to movement at a constant speed of 50 cm / sec and the last 10 cm for braking. As a result, the patient's organ to be examined, for example the heart 10, is moved by the two monochromatic beams E 1 and E 2 in a time of 250 msec. One and the same examination location is imaged so quickly in succession with the beam E 1 and the beam E 2 that the two beam images can be easily subtracted in the computer system 6.

Gemäß Figur 1 ist im Strahlengang der beiden Röntgenstrahlen zwischen dem Monochromator 1 und dem Detektor 3 noch vor dem Schnittpunkt der beiden Strahlen E1, E2 und damit vor dem zu untersuchenden Herzen 10 ein Sicherheitssystem 8 vorgesehen, das sehr schnelle Strahlverschlüsse aufweist, die die Röntgenstrahlen E1 und E2 in weniger als 10 msec absperren können. Derartige Sicherheissysteme werden beim Betrieb unseres Synchrotrons seit vielen Jahren eingesetzt. According to FIG. 1, a safety system 8 is provided in the beam path of the two X-rays between the monochromator 1 and the detector 3 before the intersection of the two beams E 1 , E 2 and thus in front of the heart 10 to be examined, which has very fast beam closures which Shut off X-rays E 1 and E 2 in less than 10 msec. Such security systems have been used in the operation of our synchrotron for many years.

Die Steuerung des Stuhls 9 erfolgt ebenfalls über das Rechnersystem 6, ohne daß dies in der Zeichnung besonders angedeutet ist. Es bereitet dem Fachmann jedoch keine Schwierigkeiten, die nicht dargestellte Hydraulik für das Anheben und Absenken des Stuhls 9 von dem Rechnersystem 6 zu steuern.The chair 9 is also controlled via the computer system 6, without this being particularly indicated in the drawing. However, it does not present any difficulties to the person skilled in the art Hydraulics shown for lifting and lowering the chair 9 to be controlled by the computer system 6.

Figur 2 zeigt einen Vertikalschnitt durch den Detektor 3 von Figur 1, der aus zwei Ionisationskammern 31, 32 mit je einer Platine 311 und 312 und einer gemeinsamen Driftkathode 313 gebildet ist.FIG. 2 shows a vertical section through the detector 3 of FIG Figure 1, the two ionization chambers 31, 32, each with one Board 311 and 312 and a common drift cathode 313 formed is.

Die beiden Ionisationskammern 31, 32 sind von einem Gehäuse 33 umschlossen, das im wesentlichen rechteckförmig ist und an einer Seite einen Befestigungsflansch 36 aufweist. Ein Einlaßkanal 37 von etwa 10mm Höhe, 150mm Breite und etwa 30mm Länge durchsetzt eine Wand des Gehäuses 33 und trägt an seinem freien Ende einen an sich bekannten Kollimator 34, durch den die beiden Strahlen E1 und E2 eintreten können. Das innere Ende des Kanals 37 ist durch ein Kohlefaserfenster (35) verschlossen.The two ionization chambers 31, 32 are enclosed by a housing 33 which is essentially rectangular and has a fastening flange 36 on one side. An inlet channel 37 of approximately 10 mm in height, 150 mm in width and approximately 30 mm in length passes through a wall of the housing 33 and carries at its free end a known collimator 34 through which the two beams E 1 and E 2 can enter. The inner end of the channel 37 is closed by a carbon fiber window (35).

Im Inneren des Gehäuses 33 befindet sich ein Hohlraum, der mit einem Ionisationsgas wie Krypton oder Xenon und einem Löschgas, z.B. Kohlendioxid unter einem Druck von 10 bis 20 bar gefüllt ist. Das Partialdruckverhältnis von Ionisationsgas zu Löschgas beträgt etwa 90:10.Inside the housing 33 there is a cavity with an ionizing gas such as krypton or xenon and an extinguishing gas, e.g. Carbon dioxide filled under a pressure of 10 to 20 bar is. The partial pressure ratio of ionization gas to extinguishing gas is about 90:10.

Wie bereits erwähnt weist jede Ionisationskammer 32 eine glasfaserverstärkte Platine 311, 312 auf, die etwa im Abstand von 9mm zueinander angeordnet sind. An den einander zugewandten Seiten der Platinen 311, 312 sind vergoldete Kupferstreifen als Anodenstreifen angeordnet, die in Strahlrichtung verlaufen und im Raster von 400 µm angeordnet sind. Im rechten Teil von Figur 2 ist der durch einen strichpunktierten Kreis hervorgehobene Teil der Platinen 311, 312 vergrößert dargestellt. Man erkennt daraus, daß zwischen den die Anodenstreifen tragenden Platinen 311, 312 eine gemeinsame Driftkathode 313 angeordnet ist und daß in dem Raum von der Driftkathode 313 zu der ersten bzw. zweiten Platine 311, 312 ein sogenanntes "Frisch-Gitter" angeordnet ist, das näher zu den Platinen 311, 312 liegt. In einer Ausführungsform hat die Driftkathode 313 eine Dicke von 1,0mm, während der Abstand zwischen der Driftkathode 313 und jeder Platine 311, 312 4,0 mm beträgt. Die beiden Frisch-Gitter 315 sind dann jeweils im Abstand von 1,0mm zu den Platinen 311, 312 und damit im Abstand von jeweils 3,0mm zur Oberfläche der Driftkathode 313 angeordnet. Frisch-Gitter bestehen aus speziellen Drähten im Abstand von 0,5mm die die in den Ionisationskammern 31, 32 gebildeten Ionen gegenüber den Anodenstreifen abschirmen.As already mentioned, each ionization chamber 32 has a glass fiber reinforced one Board 311, 312, which is approximately at a distance of 9mm are arranged to each other. On the sides facing each other The boards 311, 312 are gold-plated copper strips as anode strips arranged, which run in the beam direction and in 400 µm grid are arranged. In the right part of Figure 2 is the part highlighted by a dash-dotted circle of the boards 311, 312 shown enlarged. You can see from this that between the boards 311 carrying the anode strips, 312 a common drift cathode 313 is arranged and that in the space from the drift cathode 313 to the first and second, respectively Circuit board 311, 312 a so-called "fresh grid" is arranged, that is closer to the boards 311, 312. In one embodiment the drift cathode 313 has a thickness of 1.0 mm, during the Distance between drift cathode 313 and each circuit board 311, 312 Is 4.0 mm. The two fresh grids 315 are then each at a distance of 1.0mm to the boards 311, 312 and thus at a distance of 3.0 mm each to the surface of the drift cathode 313 arranged. Fresh grids consist of special wires in the Distance of 0.5 mm that formed in the ionization chambers 31, 32 Shield ions from the anode strips.

Die ersten und zweiten Platinen 311, 312 werden in Strahlrichtung aus dem Gehäuse 33 des Detektors 3 herausgeführt und sind an ihren Enden jeweils mit einer Nachweis-Schaltung 51, 52 verbunden. Es ist klar, daß das Gehäuse 33 des Detektors 3 verschlossen sein muß, um das Ionisationsgas und das Löschgas einschließen zu können. Zu diesem Zweck ist zwischen die Platinen 311, 312 ein Stopfen 38 eingebracht, der die beiden Platinen 311, 312 gasdicht miteinander verbindet, beispielsweise dadurch, daß er mit den Platinen 311, 312 verklebt ist. Die beiden Platinen 311, 312 sind ihrerseits mit der Wand des Gehäuses 33 gasdicht verbunden, beispielsweise ebenfalls durch Verkleben.The first and second boards 311, 312 are in the beam direction led out of the housing 33 of the detector 3 and are at their ends each connected to a detection circuit 51, 52. It is clear that the housing 33 of the detector 3 is closed must be to include the ionizing gas and the quenching gas to be able to. For this purpose is between the boards 311, 312 introduced a plug 38 which the two boards 311, 312 gas-tightly connected to one another, for example by that it is glued to the boards 311, 312. The two boards 311, 312 are in turn gas-tight with the wall of the housing 33 connected, for example also by gluing.

Wie bereits erwähnt, werden die auf den einander zugewandten Seiten der Platinen 311, 312 angeordneten Anoden als vergoldete Kupferstreifen im Raster von 400 µm aus dem Gehäuse 33 des Detektors 3 herausgeführt, und zwar in Form von 336 parallelen Streifen, die im Abstand von etwa 0,3mm angeordnet sind und die jeweils eine Breite von etwa 0,4mm haben. Die Länge jeder Platine 311, 312 beträgt etwa 230mm, während die Länge der Ionisationskammern 31, 32 etwa 60mm ausmacht.As already mentioned, those facing each other Sides of the circuit boards 311, 312 arranged as gold-plated anodes Copper strips with a grid of 400 µm from the housing 33 of the detector 3 led out, namely in the form of 336 parallel Stripes, which are arranged at a distance of about 0.3mm and the each have a width of about 0.4mm. The length of each board 311, 312 is approximately 230mm, while the length of the ionization chambers 31, 32 makes up about 60mm.

Im Inneren der Ionisationskammern 31, 32 verlaufen die Anodenstreifen über eine Länge von etwa 56mm parallel, während sie außerhalb der Ionisationskammern 31, 32 divergieren und insbesondere außerhalb des Gehäuses 33 des Detektors 3 zu einem derartigen Abstand aufgeweitet sind, daß in der Nachweis-Schaltung 51 bzw. 52 an jeden Anodenstreifen elektronische Schaltung 50. gemäß Figur 3 angeschlossen werden kann. Die beiden Nachweis-Schaltungen 51 und 52 enthalten also in einer Ausführung 2 x 336 = 672 elektronische Schaltungen 50, die den in Figur 3 gezeigten Aufbau haben.The anode strips run inside the ionization chambers 31, 32 over a length of about 56mm in parallel as they diverge outside the ionization chambers 31, 32 and in particular outside the housing 33 of the detector 3 to such a Distance are widened in the detection circuit 51 and 52 electronic circuit 50 on each anode strip. 3 can be connected. The two detection circuits In one version, 51 and 52 contain 2 x 336 = 672 electronic circuits 50, the one shown in Figure 3 Have structure.

Figur 3 zeigt eine der 2 x 336 elektronische Schaltungen 50, deren Eingang IN an einen der 2 x 336 Anodenstreifen der Platinen 311 oder 312 angeschlossen ist. Der Eingang IN der elektronische Schaltung 50 führt an den negativen Eingang eines Operationsverstärkers OPA, dessen positiver Eingang auf Masse liegt. Der Operationsverstärker OPA ist ein Typ OPA 129 UB, der von der Firma Burr-Brown hergestellt wird. Er wird normal mit ± 15 V betrieben und ist ein sehr rauscharmer Operationsverstärker.FIG. 3 shows one of the 2 x 336 electronic circuits 50, their input IN to one of the 2 x 336 anode strips on the circuit boards 311 or 312 is connected. The input IN the electronic Circuit 50 leads to the negative input of an operational amplifier OPA, the positive input of which is on ground. The operational amplifier OPA is a type OPA 129 UB, which by the Burr-Brown is manufactured. It becomes normal with ± 15 V operated and is a very low-noise operational amplifier.

An den Ausgang des Operationsverstärkers OPA ist ein Transistor T mit seinem Emmitter angeschlossen, und zwar über einen ersten Widerstand R1 von 5,1 kΩ. An der Basis des Transistors T liegt eine Gleichspannungsquelle S, die eine Gleichspannung von -4 V zur Verfügung stellt. Der Kollektor des Transistors T liegt an einem Punkt P, der im Betrieb Spannungen von 0 bis etwa 90 V sieht. Aus diesem Grunde ist der Transistor T ein spannungsfester Transistor, der als Basisschaltung eingesetzt wird. Der Kollektor des Transistors T koppelt über den Punkt P und einen zweiten Widerstand R2 von 150 MΩ auf den negativen Eingang des Operationsverstärkers OPA zurück.A transistor T with its emitter is connected to the output of the operational amplifier OPA, specifically via a first resistor R 1 of 5.1 kΩ. At the base of transistor T is a DC voltage source S, which provides a DC voltage of -4 V. The collector of the transistor T is at a point P, which sees voltages from 0 to about 90 V in operation. For this reason, the transistor T is a voltage-resistant transistor, which is used as a basic circuit. The collector of transistor T feeds back via point P and a second resistor R 2 of 150 MΩ to the negative input of the operational amplifier OPA.

An den Punkt P der elektronische Schaltung 50 wird eine hohe Gleichspannung von 100 V oder mehr gelegt, und zwar über einen dritten Widerstand R3 von beispielsweise 43 kΩ.A high DC voltage of 100 V or more is applied to the point P of the electronic circuit 50, specifically via a third resistor R 3 of 43 kΩ, for example.

Der Operationsverstärker OPA hält die Differenzspannung an seinem Eingang auf nahezu Null Volt, so daß der Strom is vom Eingangssignal über den Widerstand R2 zum Punkt P und von dort über einen vierten Widerstand R4 von 30 MΩ an einem Analog-Digital-Wandler ADC fließt. Der Analog-Digital-Wandler ist ein Baustein des Typs DDC 101 U der Firma Burr-Brown mit einer Auflösung von 20 Bit. Dieser Chip wurde speziell zum Auslesen von Photodioden konzipiert, bei denen die positiven Ladungen oder Löcher ausgelesen werden. In seinem unipolaren Betrieb ist er daher nur für die Umwandlung positiver Ladungssignale in 20 Bit-Signale einsetzbar. Der Chip DDC 101 U kann zwar auch im bipolaren Betrieb eingesetzt werden, dies reduziert die Ausgabe jedoch auf 19 Bit. In diesem Betrieb ist das Rauschen des Chips so hoch, daß man ihn für den vorliegenden Fall der Bilddarstellung nicht verwenden kann.The operational amplifier OPA keeps the differential voltage at its input at almost zero volts, so that the current i s from the input signal via the resistor R 2 to the point P and from there via a fourth resistor R 4 of 30 MΩ to an analog-to-digital converter ADC flows. The analog-digital converter is a module of the DDC 101 U type from Burr-Brown with a resolution of 20 bits. This chip was specially designed for reading photodiodes, in which the positive charges or holes are read out. In its unipolar mode, it can therefore only be used to convert positive charge signals into 20-bit signals. The DDC 101 U chip can also be used in bipolar operation, but this reduces the output to 19 bits. In this mode, the noise of the chip is so high that it cannot be used in the present case of image display.

Aus diesem Grunde kommt für die vorliegende Anwendung nur der unipolare Betrieb des Chips DDC 101 U in Frage, allerdings besteht dann die Schwierigkeit darin, daß der Chip nur positive Ladungen (Löcher) verarbeiten kann, während von den Ionisationskammern 31, 32 über die Anodenstreifen nur negative Ladungen, nämlich Elektronen, geliefert werden. Für die Erfindung ist daher wesentlich, daß aus den negativen Ladungen, die am Eingang des Operationsverstärkers OPA ankommen, positive Ladungen gemacht werden, die von dem speziellen Analog-Digital-Wandler ADC des Typs DDC 101 U verarbeitet werden können. Dazu ist es zunächst erforderlich, den am Eingang des Analog-Digital-Wandlers liegenden Widerstand R4 > 20 MΩ zu machen, denn bei kleineren Widerständen als 20 MΩ erzeugt der Chip DDC 101 U ein größeres Rauschen als das Widerstandsrauschen, das auch als Nyquist-Rauschen bezeichnet wird. Wenn das Rauschen aber bereits 4 Bit produziert, dann bleiben nur noch 16 Bit zur Bilddarstellung übrig, was zu wenig ist, um die erforderliche Bildauflösung zu erzielen.For this reason, only the unipolar operation of the DDC 101 U chip is suitable for the present application, but the difficulty then lies in the fact that the chip can only process positive charges (holes), while only from the ionization chambers 31, 32 via the anode strips negative charges, namely electrons, are supplied. It is therefore essential for the invention that the negative charges that arrive at the input of the operational amplifier OPA are turned into positive charges that can be processed by the special analog-digital converter ADC of the DDC 101 U type. To do this, it is first necessary to make the resistance R 4 > 20 MΩ at the input of the analog-digital converter, because with resistances smaller than 20 MΩ, the DDC 101 U chip generates a larger noise than the resistance noise, which is also known as Nyquist Noise is called. If the noise already produces 4 bits, then there are only 16 bits left for image display, which is too little to achieve the required image resolution.

Wählt man für den Widerstand R4 aber mehr als 20 MΩ, dann wird eine entsprechend höhere Ansteuerungsspannung am Punkt P benötigt, um den DDC 101 U in etwa 0,2 msec auf 20 Bit aufzuladen. Wählt man für den Widerstand R4 beispielsweise 30 MΩ, dann müßte die Aussteuerungsspannung am Punkt P auf bis zu 90 Volt oder mehr ansteigen können. Eine so hohe Ansteuerungsspannung kann zur Zerstörung des Operationsverstärkers OPA führen, da er nur maximal 20 bis 36 Volt vertragen kann.However, if one chooses more than 20 MΩ for the resistor R 4 , then a correspondingly higher control voltage at point P is required in order to charge the DDC 101 U to 20 bits in about 0.2 msec. If, for example, one chooses 30 MΩ for the resistor R 4 , then the modulation voltage at point P should be able to rise to up to 90 volts or more. Such a high control voltage can lead to the destruction of the operational amplifier OPA, since it can only tolerate a maximum of 20 to 36 volts.

Aus diesem Grunde wird der spannungsfeste Transistor T in Basisschaltung zwischen den Operationsverstärker OPA und den Punkt P gelegt. Die Basisschaltung bewirkt bekanntlich eine Spannungsverstärkung, wobei der Transistor T genau so stark aufsteuert, daß der Spannungsabfall über den zweiten Widerstand R2 dafür sorgt, daß die Spannungsdifferenz am Eingang des Operationsverstärkers OPA Null bzw. nahezu Null ist. Dies hat zur Folge, daß die am Operationsverstärker OPA eintreffenden Ladungen auch am Eingang des Analog-Digital-Wandlers eintreffen, und zwar in fünffacher Verstärkung, da der Widerstand R2 fünfmal so groß wie der Widerstand R4 gewählt ist. In einer bevorzugten Ausführungsform ist nämlich R2 = 150 MΩ, R4 = 30 MΩ.For this reason, the voltage-proof transistor T is placed in the basic circuit between the operational amplifier OPA and the point P. As is known, the basic circuit effects a voltage amplification, the transistor T opening up to such an extent that the voltage drop across the second resistor R 2 ensures that the voltage difference at the input of the operational amplifier OPA is zero or almost zero. The result of this is that the charges arriving at the operational amplifier OPA also arrive at the input of the analog-digital converter, in five times the amplification, since the resistance R 2 is selected five times as large as the resistance R 4 . In a preferred embodiment, R 2 = 150 MΩ, R 4 = 30 MΩ.

Das Wesen der erfindungsgemäßen elektronischen Schaltung 50 besteht also in folgenden Maßnahmen:

  • 1. Negative Ladungen werden in positive Ladungen umgewandelt, um von dem Chip DDC 101 U verarbeitet werden zu können.
  • 2. Die Ansteuerungsspannung für den ADC-Chip wird auf bis zu 90 Volt oder mehr gewählt.
  • 3. Die hohe Ansteuerungsspannung für den ADC wird durch eine Basisschaltung vom Operationsverstärker abgehalten.
    • The essence of the electronic circuit 50 according to the invention thus consists in the following measures:
  • 1. Negative charges are converted into positive charges in order to be processed by the DDC 101 U chip.
  • 2. The drive voltage for the ADC chip is selected to be up to 90 volts or more.
  • 3. The high drive voltage for the ADC is kept away from the operational amplifier by a basic circuit.

    • Dadurch wird ein Signal: Rausch - Verhältnis von 300.000 : 1 erreicht, was für die Klarheit der Abbildung für den diagnostizierenden Arzt ausreicht. Die von den Ionisationskammern 31, 32 auf den Anodenstreifen gelieferten Signalströme liegen im übrigen im Bereich von 100 fA oder weniger, also imax < 100 x 10-15A. Diese Ströme sind so gering, daß sie einzelnen 33keV Photonen entsprechen.This achieves a signal: noise ratio of 300,000: 1, which is sufficient for the clarity of the image for the diagnosing doctor. The signal currents supplied by the ionization chambers 31, 32 on the anode strips are otherwise in the range of 100 fA or less, ie i max <100 x 10 -15 A. These currents are so low that they correspond to individual 33 keV photons.

    Claims (9)

    1. Arrangement for digital subtraction angiography in the energy subtraction mode comprising a monochromator (1) for generating two monochromatic X-ray beams (E1, E2); comprising a safety system (8) with very rapid beam shutters; comprising a line scan device driven by a hydraulics system, on which a chair (9), which can be moved up and down for positioning a patient, is mounted; comprising a two-line detector (3); comprising a computer system (6) for system control, data acquisition and image processing; characterised in that the detector (3) is formed by two locally resolving ionisation chambers (31, 32), which are filled with an ionisation gas and which have a certain number of anode strips (311, 312); in that a common drift cathode (313) is used for both ionisation chambers (31, 32); in that a separate detection circuit (51, 52), each with an electronic circuit (50) for each anode strip (311, 312), is connected to each ionisation chamber (31, 32), which detection circuits operate linearly as a signal converter between 0 and 175 volts; in that each electronic circuit (50) has an operational amplifier (OPA) at its input, to the negative input of which the input signal from the anode strips (311, 312) is applied, while the positive input is earthed; in that the output of the operational amplifier (OPA) is connected via a first resistance (R1) to the emitter of a transistor (T), at the base of which there is a DC voltage source (S), and the collector of which is connected via a point (P) and a fourth resistance (R4) to the input of an analogue-digital converter (ADC); in that the fourth resistance (R4) is greater than 20 MΩ; in that a DC voltage of 100 v or more is applied to the point (P) via a third resistance (R3); in that between the input of the operational amplifier (OPA) and the point (P), there is a second resistance (R2), which passes the input signal current (is) finally to the analogue-digital converter (ADC); and in that the outputs of all the electronic circuits (50) are transmitted as bit words via a bus system (511, 512) to the computer system (6).
    2. Arrangement according to claim 1, characterised in that the analogue-digital converter (ADC) is a 20-bit charge digital converter.
    3. Arrangement according to either of claims 1 and 2, characterised in that the fourth resistance (R4) has 30 MOhm and the second resistance (R2) has 150 MOhm.
    4. Arrangement according to claim 1, characterised in that the first resistance (R1) has 5.1 kOhm and the third resistance (R3) has 43 kOhm.
    5. Arrangement according to claim 4, characterised in that there is approximately + 145 v DC voltage at the side of the third resistance (R3) remote from point (P).
    6. Arrangement according to any one of claims 1 to 5, characterised in that the transistor (T) operated as a base circuit is a transistor that is voltage-stable up to about 200 v.
    7. Arrangement according to claim 6, characterised in that the DC voltage source (S) applies a DC voltage of less than -1 v to the base of the transistor (T).
    8. Arrangement according to any one of claims 1 to 7, characterised in that the operational amplifier (OPA) is formed from a Difet circuit.
    9. Arrangement according to claim 1, characterised in that the detector (3) has a number of 336 signal leads for each energy (E1, E2).
    EP98966282A 1997-12-22 1998-12-14 Device for digital subtraction angiography Expired - Lifetime EP1042689B1 (en)

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    DE19758363A DE19758363C2 (en) 1997-12-22 1997-12-22 Arrangement for digital subtraction angiography
    DE19758363 1997-12-22
    PCT/EP1998/008037 WO1999032901A1 (en) 1997-12-22 1998-12-14 Device for digital subtraction angiography

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    EP1042689A1 EP1042689A1 (en) 2000-10-11
    EP1042689B1 true EP1042689B1 (en) 2004-03-03

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    CN1172194C (en) 2004-10-20
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    DK1042689T3 (en) 2004-05-10
    JP2001526921A (en) 2001-12-25
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    DE19758363A1 (en) 1999-07-01
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    EP1042689A1 (en) 2000-10-11
    WO1999032901A1 (en) 1999-07-01

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